PROJECT SUMMARY/ABSTRACT Frontotemporal dementia (FTD) is marked by profound impairments in decision-making; unfortunately, FTD is typically only diagnosed after patients have made significant errors in judgment. Clinically, delays in diagnosis reflect the absence of objective clinical tests for decision-making, and are missed opportunities to prevent serious harms. Scientifically, delayed diagnosis limits our ability to study decision-making deficits, as research patients with confirmed FTD tend to have more profound deficits that may not reflect early changes, and often cannot tolerate more sophisticated behavioral paradigms. This clinical and scientific gap will be addressed with neuroeconomic analyses of decision-making in presymptomatic mutation carriers from familial FTD kindreds in two large NIH-funded multicenter networks spanning the US and Canada. The central hypothesis is that early behavioral and physiological changes in FTD mutation carriers will reveal initial signs and mechanisms of impaired judgment in FTD, potentially also elucidating neural mechanisms of impaired decision-making in other neuropsychiatric disorders. 110 presymptomatic carriers and 110 noncarrier family members from these multicenter networks will be recruited for tests of decision-making on a secure web-enabled platform that enables rapid and flexible data collection from participants across North America. Guided by strong preliminary data, the central hypothesis will be tested by pursuing three specific aims: 1) Apply neuroeconomic models of decision-making to define subtle alterations in judgment in presymptomatic bvFTD mutation carriers; 2) Determine structural and functional (resting-state) MRI predictors of altered decision- making in bvFTD mutation carriers; and 3) Elucidate neural and physiological mechanisms underlying behavioral change in mutation carriers. Under the first two aims, the web-enabled platform will assay neuroeconomic parameters such as loss aversion, framing effects, and interpersonal decision-making; which will then be analyzed in conjunction with a rich dataset of cognitive and neuroimaging measures already being collected per protocol across network sites. Under Aim 3, behavioral performance on the web-enabled platform will be used to select a subset of mutation carriers and noncarriers for more detailed in-person physiological and task-based fMRI testing. This web-enabled approach is innovative, because while other researchers have begun to use online methods to administer tasks to large numbers of participants at home, this strategy allows the evaluation of hypotheses involving neuroimaging and standardized measures that cannot be performed online. This combines the strengths of traditional on-site evaluation with the flexibility and scaling advantages of newer online methods. The proposed work will thus make a significant contribution by applying novel methods and more precise neuroeconomic measures of decision-making in a large sample of presymptomatic gene carriers, addressing a major limitation to research on some of the earliest and most damaging symptoms of FTD.